Pharmaceutical composition for piperidinoalkanol compounds

ABSTRACT

The invention provides a pharmaceutical composition in solid unit dosage form, comprising, a) a therapeutically effective amount of a piperidinoalkanol compound or a pharmaceutically acceptable salt thereof; and, b) at least one inert ingredient.

This is a Continuation of application Ser. No. 10/347,953, filed Jan.21, 2003, which is a Continuation of application Ser. No. 10/039,798,filed Jan. 4, 2002, which is a Continuation of application Ser. No.09/845,966, filed Apr. 30, 2001, now abandoned, which is a Continuationof application Ser. No. 09/586,743, filed Jun. 2, 2000, now abandoned,which is a Continuation of application Ser. No. 09/157,841, filed Sep.21, 1998, issued as U.S. Pat. No. 6,113,942 on Sep. 5, 2000, which is aDivisional Application of Ser. No. 08/943,460, filed Oct. 3, 1997,issued as U.S. Pat. No. 5,855,912 on Jan. 5, 1999, which is aContinuation of application Ser. No. 08/552,287, filed Dec. 12, 1995,now Abandoned, which is a Continuation-In-Part of application Ser. No.08/395,952, filed Feb. 28, 1995, now abandoned, all of which areincorporated by reference.

BACKGROUND OF THE INVENTION

It has been established that various piperidinoalkanol compounds areuseful as antihistamines, antiallergy agents and bronchodilators asdisclosed in U.S. Pat. Nos. 3,878,217, 4,254,129 and 4,285,957. Severalexamples of formulations of these various piperidinoalkanol compoundsare described below.

In U.S. Pat. No. 4,929,605, J. Domet and D. Shah describe apharmaceutical composition in solid unit dosage form, comprising, atherapeutically effective amount of a piperidinoalkanol compound, or apharmaceutically acceptable salt thereof, a pharmaceutically acceptablenonionic or cationic surfactant in an amount of from about 0.1% to about6% by weight of the composition, and a pharmaceutically acceptablecarbonate salt in an amount of from about 2% to about 50% by weight ofthe composition.

N. Webb and G. Hammer describe in U.S. Pat. No. 4,996,061, apharmaceutical composition in the form of a multiple-compression tabletcomprising a discrete zone made from a formulation which providessustained-release of a therapeutically effective decongestant amount ofa sympathomimetic drug and a discrete zone made from a differentformulation which provides immediate release of a therapeuticallyeffective antihistaminic amount of a piperidinoalkanol and, optionally,a therapeutically effective decongestant amount of a sympathomimeticdrug.

Efforts have focused on improving the bioavailability of variouspiperidinoalkanol compounds in order to improve their therapeuticefficiency. The present invention relates to pharmaceutical compositionsand pharmaceutical compositions in solid unit dosage form wherein thepiperidinoalkanol compound, or a pharmaceutically acceptable saltthereof, is in combination with inert ingredients.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition in solidunit dosage form, comprising,

a) a therapeutically effective amount of a piperidinoalkanol compound ora pharmaceutically acceptable salt thereof; and

b) at least one inert ingredient.

The present invention further provides a pharmaceutical compositionprepared by a wet granulation process comprising, preparing the wetgranulation wherein a compound of the formula;

wherein X is a number ranging from about zero to 5, and the individualoptical isomers thereof, a diluent and a disintegrant are mixed with asolution of a binding agent; the wet granulation is screened; and thewet granulation is dried. In addition, the present invention providescombining the above dry granulation with a lubricant. The presentinvention further provides pressing the above final mixture into atablet.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the terms “piperidinoalkanol compounds” and“piperidinoalkanol compounds and their pharmaceutically acceptablesalts” refers to those compounds described by formulas (I), (II) and(III) which are disclosed in U.S. Pat. Nos. 3,878,217, 4,254,129 and4,285,957 the disclosure of each patent being incorporated herein byreference. In addition, the patent application entitled “PharmaceuticalComposition Piperidinoalkanol Compounds”, U.S. Ser. No. 08/395,952,filed Feb. 28, 1995 is incorporated herein by reference.

Piperidinoalkanol compounds of formula (I) are those which correspond tothe formula;

wherein R₁ is hydrogen or hydroxy; R₂ is hydrogen; or R₁ and R₂ takentogether form a second bond between the carbon atoms bearing R₁ and R₂;n is a positive whole integer of from 1 to 3; Z is thienyl, phenyl orsubstituted phenyl wherein the substituents on the substituted phenylmay be attached at the ortho, meta or para positions of theunsubstituted phenyl ring and are selected from the group consisting ofa halogen atom, a straight or branched lower alkyl chain of from 1 to 4carbon atoms, a lower alkoxy group of from 1 to 4 carbon atoms, adi(lower)alkylamino group, or a saturated monocyclic heterocyclic ringselected from the group consisting of pyrrolidino, piperidino,morpholino, or N-(lower)alkylpiperizino, or pharmaceutically acceptableacid addition salts thereof.

Piperidinoalkanol compounds of formula (II) are those which correspondto the formula;

wherein R₁ represents hydrogen or hydroxy; R₂ represents hydrogen; or R₁and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂; m is an integer of from 1 to 5; R₃ is —CH₃, or—CH₂OH; each A and B is hydrogen or hydroxy; with the provisos that atleast one of A or B is hydrogen and one of A or B is other than hydrogenwhen R₃ is —CH₃; and pharmaceutically acceptable salts and individualoptical isomers thereof.

Piperidinoalkanol compounds of formula (III) are those which correspondto the formula;

wherein R₁ represents hydrogen or hydroxy; R₂ represents hydrogen; or R₁and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂; m is an integer of from 1 to 5; R₄ is —CO₂H or—CO₂alkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and isstraight or branched; each of A and B is hydrogen or hydroxy; with theproviso that at least one of A or B is hydrogen; and pharmaceuticallyacceptable salts and individual optical isomers thereof.

More specifically,4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride of formula (IIIa)

wherein X is a number ranging from about zero to 5, and the individualoptical isomers thereof, is a preferred piperidinoalkanol compound. Thecompound4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride wherein X is zero or one in formula (IIIa) is themost preferred piperidinoalkanol compound.

In addition, the free base of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid of formula (IIIb)

wherein X is a number ranging from about zero to 5, and the individualoptical isomers thereof, is also a preferred piperidinoalkanol compound.

Further included within the scope of the piperidinoalkanol compounds offormulas (III), (IIIa) and (IIIb) are the polymorphic, pseudomorphic andamorphous forms, and mixtures thereof. More specifically, the polymorphsof anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which are designated herein as Form I and Form III.The Form I polymorph of anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride may be identified by the following characteristics: avisual melting point (capillary tube) in the range of about 196-201° C.;a melt endotherm with extrapolated onset in the range of about 195-199°C. as determined by differential scanning calorimetry; and an X-raypowder diffraction pattern essentially as shown in Table 1 wherein theXRPD patterns were measured using a powder diffractometer equipped witha Co X-ray tube source. The sample was illuminated with Co Kα₁ radiationand XRPD data were collected from 5 to 55° 2θ. (intensities may varyradically due to preferred orientation).

TABLE 1 D-Space, Intensity, Angstroms I/I_(o), % 11.8 30 7.3 30 6.3 655.9 35 5.0 45 4.8 100 4.4 45 3.9 60 3.8 75 3.7 30

The Form III polymorph of anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride may be identified by the following characteristics: avisual melting point (capillary tube) in the range of about 166-171° C.;a broad endotherm below about 90° C., a melt endotherm with anextrapolated onset of about 166° C. as determined by differentialscanning calorimetry; and an X-ray powder diffraction patternessentially as shown in Table 2 wherein the XRPD patterns were measuredusing a powder diffractometer equipped with a Co X-ray tube source. Thesample was illuminated with Co Kα₁ radiation and XRPD data werecollected from 5 to 55° 2θ. (intensities may vary radically due topreferred orientation).

TABLE 2 D-Space, Intensity, Angstroms I/I_(o), % 9.0 95 4.9 100 4.8 354.6 25 4.5 25 3.7 25

In addition, the psuedomorphs of hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride are designated herein as Form II and Form IV. TheForm II pseudomorph of hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride may be identified by the following characteristics: avisual melting point (capillary tube) in the range of about 100-105° C.;a large broad endotherm below about 100° C. and a small endothermic peak(about 2 joules/gram) with extrapolated onsets in the range of about124-126° C. as determined by differential scanning calorimetry; and anX-ray powder diffraction pattern essentially as shown in Table 3 whereinthe XRPD patterns were measured using a powder diffractometer equippedwith a Co X-ray tube source. The sample was illuminated with Co Kα₁radiation and XRPD data were collected from 5 to 55° 2θ. (intensitiesmay vary radically due to preferred orientation).

TABLE 3 D-Space, Intensity, Angstroms I/I_(o), % 7.8 45 6.4 44 5.2 854.9 60 4.7 80 4.4 55 4.2 50 4.1 60 3.7 75 3.6 60 3.5 50

The Form IV pseudomorph of hydrated4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride may be identified by the following characteristics: avisual melting point (capillary tube) in the range of about 113-118° C.;two broad overlapping endotherms below about 100° C. and an additionalendotherm with an extrapolated onset at approximately 146° C. asdetermined by differential scanning calorimetry and an X-ray powderdiffraction pattern essentially as shown in Table 4 wherein the XRPDpatterns were measured using a powder diffractometer equipped with a CoX-ray tube source. The sample was illuminated with Co Kα₁ radiation andXRPD data were collected from 5 to 55° 2θ. (intensities may varyradically due to preferred orientation).

TABLE 4 D-Space, Intensity, Angstroms I/I_(o), % 10.4 60 7.0 45 6.4 505.3 100 5.2 55 4.3 75 4.1 50 4.0 45 3.8 60 3.5 55

Included within the scope of the present invention are the pseudomorphsand polymorphs of the hydrated and anhydrous free base of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid. The free base of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid is readily prepared utilizing techniques and procedures well knownto one of ordinary skill in the art. For example, the hydrochloride saltof4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid is dissolved in methanol and treated with one equivalent of aqueoussodium bicarbonate. After stirring for approximately 5 to 30 minutes,the white solid is collected by filtration, rinsed with water and airdried to provide the dihydrate of the free base of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid.

Illustrative examples of straight or branched alkyl groups having from 1to 4 carbon atoms referred to herein are methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl and t-butyl. Illustrative examples ofstraight or branched alkyl groups having from 1 to 6 carbon atomsreferred to herein are methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, n-pentyl, cyclopentyl, n-hexyl and cyclohexyl.Illustrative examples of lower alkoxy groups of from 1 to 4 carbon atomsreferred to herein are methoxy, ethoxy, propoxy, n-butoxy, isobutoxy,sec-butoxy and t-butoxy. The terms “halo”, “halogen” or “halide” refersto a fluorine, chlorine, bromine or iodine atom.

The term “pharmaceutically acceptable salt” refers to those salts offormulas (I), (II), (III) and (IIIa) that are not substantially toxic atthe dosage administered to achieve the desired effect and do notindependently possess significant pharmacological activity. The saltsincluded within the scope of this term are pharmaceutically acceptableacid addition salts of a suitable inorganic or organic acid. Suitableinorganic acids are, for example hydrochloric, hydrobromic, sulfuric andphosphoric acids. Suitable organic acids include carboxylic acids, suchas acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic,fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic,hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic,4-hydroxybenzoic, anthranillic, cinnamic, salicylic, 4-aminosalicyclic,2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acid, sulfonic acids,such as methanesulfonic, ethanesulfonic and -hydroxyethanesulfonic acid.In addition, pharmaceutically acceptable salts include those salts offormulas (I), (II), (III) and (IIIa) formed with inorganic and organicbases, such as those of alkali metals, for example sodium, potassium andlithium, alkaline earth metals, for example calcium and magnesium, lightmetals of group IIIA, for example aluminum, organic amines, for exampleprimary, secondary or tertiary amines, such as cyclohexylamine,ethylamine, pyridine, methylaminoethanol and piperazine. The salts areprepared by conventional means by one of ordinary skill in the art as,for example, by treating a compound of formulas (I), (II), (III) or(IIIa) with an appropriate acid or base. Such salts can exist in eithera hydrated or substantially anhydrous form.

As used herein, the phrase “formulas I through IIIb” refers to formulasI, II, III, IIIa and IIIb.

As used herein, the term “azeotropic mixture” refers to a liquid mixtureof two or more substances which behaves like a single substance in thatthe vapor produced by partial evaporation of liquid has the samecomposition as the liquid. The constant boiling mixture exhibits eithera maximum or minimum boiling point as compared with that of othermixtures of the same substance.

As used herein, the term “azeotropic distillation” refers to a type ofdistillation in which a substance is added to the mixture to beseparated in order to form an azeotropic mixture with one or more of theconstituents of the original mixture. The azeotrope or azeotropes thusformed will have boiling points different from the boiling points of theoriginal mixture. As used herein, the term “azeotropic distillation”also refers to co-distillation.

As used herein, the term “water-minimizing recrystallization” refers toa recrystallization wherein the ratio of anhydrous solvent to substratehydrate is such that the percentage of water present is minimized,thereby inducing precipitation of the anhydrous form of the substrate.

As used herein, the term “aqueous recrystallization” refers to thoseprocesses wherein either 1) a solid material is dissolved in a volume ofwater or a water/organic solvent mixture sufficient to cause dissolutionand the solid material recovered by evaporation of the solvent; 2) asolid material is treated with a minimal amount of water or awater/organic solvent mixture which is not sufficient to causedissolution, heated to obtain dissolution and cooled to inducecrystallization or 3) a solid material is dissolved in a volume of wateror a water/organic solvent mixture sufficient to cause dissolution andthen the solvent is partially evaporated to form a saturated solutionwhich induces crystallization.

As used herein, the term “crystal digestion” refers to that processwherein a solid material is treated with a minimal amount of water orwater/organic solvent mixture which is not sufficient to causedissolution and either heating or stirring at ambient temperature untilthe desired transformation has taken place.

As used herein, the term “antisolvent” refers to a poor solvent for thesubstance in question which when added to a solution of the substance,causes the substance to precipitate.

As used herein, the term “suitable temperature” refers to thattemperature which is sufficient to cause dissolution and to permit theprecipitation of the desired substance either upon addition of anantisolvent or upon removal of the co-solvent by azeotropicdistillation.

The term “micronization” refers to the process of increasing theparticle surface area of the piperidinoalkanol compounds or theirpharmaceutically acceptable salts to greater than about 1.0 m²/g.

The piperidinoalkanol compounds of formulas (I) through (IIIb) which arenot subjected to micronization have a particle surface area of less thanabout 1.0 m²/g.

The pharmaceutical composition of the present invention is administeredorally in the form of a solid unit dosage form. Examples of solid unitdosage forms are tablets, coated tablets, powders, dragees, hard or softgelatin capsules and the like. The preferred solid unit dosage forms ofthe present invention are capsules, tablets and the like. The mostpreferred solid unit dosage form is tablets. A unit dose is that amountof the pharmaceutical composition which is individually administered.The pharmaceutical compositions of the present invention are useful asantihistamines, antiallergy agents, bronchodilators and in the treatmentof urticaria.

As used herein, the term “patient” refers to a warm-blooded animal, suchas a mammal, which is in need of an antihistamine, antiallergy agent,bronchodilator or treatment of urticaria. It is understood that humans,mice and rats are included within the scope of the term “patient”.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use of knowntechniques and by observing results obtained under analogouscircumstances. In determining the therapeutically effective amount ordose, a number of factors are considered by the attending diagnostician,including, but not limited to: the species of mammal; its size, age, andgeneral health; the response of the individual patient; the particularcompound administered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances.

A therapeutically effective amount of a piperidinoalkanol compound offormulas (I) through (IIIb) is that amount which produces the desiredtherapeutic response (ie., antihistaminic, antiallergic, bronchodilatoryeffect, or reduction or elimination of urticaria) upon oraladministration according to a single or multiple dosage regimen. Atherapeutically effective amount of a piperidinoalkanol compound offormulas (I) through (IIIb) may vary over a wide range from about 0.01milligrams per kilogram (mg/kg) to about 20 (mg/kg) of body weight perdose. A pharmaceutical composition which provides from about 5 mg toabout 360 mg of a piperidinoalkanol compound of formulas (I) through(IIIb) per unit dose is preferred and those which provide from about 40mg to about 240 mg per unit dose are most preferred.

According to the present invention the piperidinoalkanol compounds offormulas (I) through (IIIb) when micronized have a particle surface areaof greater than about 1.0 m2/g. The preferred particle surface area whenmicronized is about 2 to 10 m²/g, the most preferred particle surfacearea when micronized is about 2 to 6 m²/g and the most especiallypreferred particle surface area of the piperidinoalkanol compounds offormulas (I) through (IIIb) when micronized is about 2 to 4 m²/g.

The piperidinoalkanol compounds of formulas (I) through (IIIb) arereadily prepared by one of ordinary skill in the art, for example,utilizing the techniques and procedures described in U.S. Pat. Nos.3,878,217, 4,254,129 and 4,285,957, International Application NumberPCT/US93/02103 published Oct. 28, 1993, WO 93/21156, and InternationalApplication Number PCT/US94/05982, published Jan. 5, 1995, WO 95/00480which are incorporated herein by reference.

The anhydrous, pharmaceutically acceptable acid addition salts of thepiperidinoalkanol compounds of the formulas (III), and (IIIa) may beprepared from the corresponding hydrated, pharmaceutically acceptableacid addition salts of the piperidinoalkanol compounds of the formulas(III) and (IIIa) by subjecting the corresponding hydrated,pharmaceutically acceptable acid addition salts of the piperidinoalkanolcompounds of the formulas (III) and (IIIa) to an azeotropicdistillation.

For example, the appropriate hydrated, pharmaceutically acceptable acidaddition salt of the piperidinoalkanol compounds of the formulas (III)and (IIIa) is first dissolved in a volume of a suitable solvent orsolvent mixture which is sufficient to cause dissolution. Examples ofsuch solvents are water, C₁-C₅ alkanols such as methanol, ethanol andthe like; ketone solvents such as acetone, methyl ethyl ketone and thelike; aliphatic ester solvents such as ethyl acetate, methyl acetate,methyl formate, ethyl formate, isopropyl acetate and the like andaqueous mixtures of these solvents, such as acetone/water, methyl ethylketone/water, water/acetone and water/acetone/ethyl acetate. Anadditional volume of the same solvent used to effect dissolution orsecond suitable anhydrous antisolvent is then added to this solution,which is then heated to a boiling point which is suitable toazeotropically remove water and other low boiling components. Suitableanhydrous antisolvents for use in the azeotropic distillation are, forexample, ketone solvents such as acetone, methyl ethyl ketone and thelike; aliphatic ester solvents such as ethyl acetate, methyl acetate,methyl formate, ethyl formate, isopropyl acetate and the like; C₅-C₈aliphatic solvents such as pentane, hexane and the like; aliphaticnitrites, such as acetonitrile and mixtures of these solvents such asacetone/ethyl acetate and the like. The azeotropic mixture of water andsolvent is removed by distillation until the temperature changes,indicating that the azeotropic mixture is completely removed. Thereaction mixture is cooled and the corresponding anhydrous,pharmaceutically acceptable acid addition salts of the piperidinoalkanolcompounds of the formulas (III) and (IIIa) is recovered from thereaction zone by, for example filtration.

In addition, the anhydrous, pharmaceutically acceptable acid additionsalts of the piperidinoalkanol compounds of the formulas (III) and(IIIa) may be prepared from the corresponding hydrated, pharmaceuticallyacceptable acid addition salts of the piperidinoalkanol compounds of theformulas (III) and (IIIa) by subjecting the corresponding hydrated,pharmaceutically acceptable acid addition salts of the piperidinoalkanolcompounds of the formulas (III) and (IIIa) to a water-minimizingrecrystallization.

For example, the appropriate hydrated, pharmaceutically acceptable acidaddition salt of the piperidinoalkanol compounds of the formulas (III)and (IIIa) is dissolved in a volume of a suitable anhydrous solvent orsolvent mixture which is sufficient to cause dissolution and heated toreflux. Examples of such solvents are water, C₁-C₅ alkanols such asmethanol, ethanol and the like; ketone solvents such as acetone, methylethyl ketone and the like; aliphatic ester solvents such as ethylacetate, methyl acetate, methyl formate, ethyl formate, isopropylacetate and the like and aqueous mixtures of these solvents, such asacetone/water, methyl ethyl ketone/water, water/acetone andwater/acetone/ethyl acetate. An additional volume of the same solventused to effect dissolution or second suitable anhydrous antisolvent isthen added in a quantity sufficient to initiate precipitation of theanhydrous, pharmaceutically acceptable acid addition salt of thepiperidinoalkanol compounds of the formulas (III) and (IIIa). Suitableanhydrous antisolvents are, for example, ketone solvents such asacetone, methyl ethyl ketone and the like; aliphatic ester solvents suchas ethyl acetate, methyl acetate, methyl formate, ethyl formate,isopropyl acetate and the like; mixtures of ketone solvents andaliphatic ester solvents such as acetone/ethyl acetate and the like;C₅-C₈ aliphatic solvents such as pentane, hexane and the like; aliphaticnitriles, such as acetonitrile and mixtures of these solvents such asacetone/ethyl acetate and the like as well as mixtures of water andketone solvents such as acetone/water and the like; and mixtures ofwater, ketone solvents and aliphatic ester solvents such asacetone/water/ethyl acetate. The reaction mixture is cooled and thecorresponding anhydrous, pharmaceutically acceptable acid addition saltof the piperidinoalkanol compounds of the formulas (III) and (IIIa) isrecovered from the reaction zone by, for example filtration.

Polymorphic forms of anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Forms I and III) may be prepared by a variety ofmethods as detailed below.

Form III to Form I

For example, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) may be prepared from anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III), by subjecting the anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III) to a crystal digestion as described above.

Form II to Form III

In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III) may be prepared from hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II), by subjecting the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to water-minimizing recrystallization asdescribed above.

Form II to Form I

In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) may be prepared from hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II), by subjecting the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to water-minimizing recrystallization asdescribed above or by subjecting the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to an azeotropic distillation.

Form IV to Form I

In addition, anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) may be prepared from hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV), by subjecting the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV) to water-minimizing recrystallization or toan azeotropic distillation as described above.

The hydrated, pharmaceutically acceptable acid addition salts of thepiperidinoalkanol compounds of the formulas (III) and (IIIa) may beprepared from the corresponding compound of the formula (IV)

wherein R₁ represents hydrogen or hydroxy; R₂ represents hydrogen; or R₁and R₂ taken together form a second bond between the carbon atomsbearing R₁ and R₂; m is an integer of from 1 to 5; R₄ is —CO₂alkylwherein the alkyl moiety has from 1 to 6 carbon atoms and is straight orbranched; each of A and B is hydrogen or hydroxy; with the proviso thatat least one of A or B is hydrogen; by subjecting the correspondingcompound of formula (IV) to a reduction using an appropriate reducingagent, such as sodium borohydride, potassium borohydride, sodiumcyanoborohydride, or tetramethylammonium borohydride in a suitablesolvent, such as, methanol, ethanol, isopropyl alcohol or n-butanol,aqueous mixtures thereof or basic solutions thereof, at temperaturesranging from about 0° C. to the reflux temperature of the solvent, andthe reaction time varies from about ½ hour to 8 hours. After quenchingand acidifying with an suitable acid, such as hydrochloric acid, thehydrated, pharmaceutically acceptable acid addition salts of thepiperidinoalkanol compounds of the formulas (III) and (IIIa) arerecovered from the reaction zone by crystallization and filtration.

In addition, the hydrated, pharmaceutically acceptable acid additionsalts of the piperidinoalkanol compounds of the formulas (III) and(IIIa) may be prepared from the corresponding anhydrous,pharmaceutically acceptable acid addition salts of the formulas (III),(IIIa) and (IIIb) by subjecting the corresponding anhydrous,pharmaceutically acceptable acid addition salts of formulas (III) and(IIIa) to an aqueous recrystallization.

For example, the appropriate anhydrous, pharmaceutically acceptable acidaddition salt of the piperidinoalkanol compounds of the formula (I) and(II) is treated with a minimal volume of water or suitable water/organicsolvent mixture which is insufficient to cause dissolution and heated toreflux. The reaction mixture is cooled and the corresponding hydrated,pharmaceutically acceptable acid addition salt of the piperidinoalkanolcompounds of the formulas (III) and (IIIa) is recovered from thereaction zone by, for example filtration. Alternatively, the appropriateanhydrous, pharmaceutically acceptable acid addition salt of thepiperidinoalkanol compounds of the formulas (III) and (IIIa) is treatedwith a volume of water or a suitable water/organic solvent mixture whichis sufficient to cause dissolution and the water or water/organicsolvent is partially or completely evaporated to a volume which inducescrystallization of the hydrated, pharmaceutically acceptable acidaddition salts of the piperidinoalkanol compounds of the formulas (III)and (IIIa). Suitable solvents for use in the above recrystallization arewater, acetone/water, ethanol/water, methyl ethyl ketone/aqueousmethanol, methyl ethyl ketone/water and the like.

The pseudomorphic forms of hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Forms II and IV) may be prepared by a variety ofmethods as detailed below.

Ethyl Ester/Ketone to Form II

Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV) may be prepared from ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride or free base as described above for the generalpreparation of the hydrated, pharmaceutically acceptable acid additionsalts of the piperidinoalkanol compounds of the formula (III) from thecorresponding compound of the formula (IV) wherein R₃ is —COOalkyl, andrapidly adding water over a period of time ranging from 1 minute to 45minutes at a temperature range of about −20° C. to 50° C. to precipitatethe hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II).

Ethyl Ester/Ketone to Form IV

Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV) may be prepared from ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride or free base as described above for the generalpreparation of the hydrated, pharmaceutically acceptable acid additionsalts of the piperidinoalkanol compounds of the formula (III) from thecorresponding compound of the formula (IV) wherein R₃ is —COOalkyl,slowly adding water over a period of time ranging from about 30 minutesto 24 hours and at a temperature range of about 0° C. to 50° C.,optionally with seeding, to precipitate the hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form IV).

Form I to Form II

Hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) may be prepared from anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) by subjecting hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form II) to an aqueous recrystallization as definedabove.

Starting materials for use in the present invention are readilyavailable to one of ordinary skill in the art. For example, ethyl4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride is described in U.S. Pat. No. 4,254,129, Mar. 3, 1981.

Preparation of the Piperidinoalkanol Compounds of Formulas (I) Through(IIIb) with the desired particle surface area is readily performed byone of ordinary skill in the art. For example, the particle surface areacan be increased by milling the piperidinoalkanol compounds with a JetMill (Jet-O-Mizer®, Fluid Energy Processing and Equipment Company,Hatfield, Pa.). Similar mills, such as the Micro-Jet (Fluid EnergyProcessing and Equipment Company) and the Sturtevant Micronizer(Sturtevant, Boston, Mass.) may also be used. With the Jet Mill, thepiperidinoalkanol compound particles are accelerated in a millingchamber using compressed air. Piperidinoalkanol compound particlesurface area is increased by particle-to-particle impact. The mill isdesigned such that the particles exit the milling chamber and arecollected in a collection vessel. Fine particles are also collected in afilter bag. The particle surface area of the milled piperidinoalkanolcompound is influenced by the pressure of the compressed air and by thefeed of the piperidinoalkanol compound into the mill. Increased particlesurface area may also be achieved by controlled crystallization of thepiperidinoalkanol compound under conditions determined by one ofordinary skill in the art.

The particle surface area of the piperidinoalkanol compounds of formulas(I) through (IIIb) can be readily determined by one of ordinary skill inthe art. For example, the surface area can be determined by the BETmethod (see S. Brunauer, P. H. Emmet and E. Teller, J. Amer. Chem. Soc.,60 (1938) 309-319). A gas adsorption instrument, such as the Quantasorb®Gas Sorption System (Quantachrome Corp., Syosset, N.Y. 11791) can beused to perform a multi-point analysis using nitrogen adsorption.

As used herein the term “inert ingredient” refers to thosetherapeutically inert ingredients that are well know in the art ofpharmaceutical science which can be used singly or in variouscombinations, and include, for example, binders, diluent, lubricants,glidants, sweetening agents, disintegrants, coloring agents flavoringagents, antioxidants, solubilizing agents, coating agents and the like,as are disclosed in The United States Pharmacopia, XXII, 1990, (1989 TheUnited States Pharmacopia Convention, Inc.), pages 1857-1859, which areacidifying agent including acetic acid, glacial acetic acid, citricacid, fumaric acid, hydrochloric acid, diluted hydrochloric acid, malicacid, nitric acid, phosphoric acid, phosphoric acid diluted, sulfuricacid and tartaric acid; aerosol propellant including butane,dichlorodifluoromethane, dichlorotetrafluoroethane, isobutane, propaneand trichloromonofluoromethane; air displacement including carbondioxide and nitrogen; alcohol denaturant including denatonium benzoate,methyl isobutyl ketone and sucrose octaacetate; alkalizing agentincluding strong ammonia solution, ammonium carbonate, diethanolamine,diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodiumborate, sodium carbonate, sodium hydroxide and trolamine; antifoamingagent including dimethicone and simethicone; antimicrobial preservativeincluding benzalkonium chloride, benzalkonium chloride solution,benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben,cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol,dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium,phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuricnitrate, potassium benzoate, potassium sorbate, propylparaben,propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodiumpropionate, sorbic acid, thimerosal and thymol; antioxidant includingascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate,sodium formaldehyde sulfoxylate, sodium metabisulfite, sodiumthiosulfate, sulfur dioxide, tocopherol and tocopherols excipient;buffering agent including acetic acid, ammonium carbonate, ammoniumphosphate, boric acid, citric acid, lactic acid, phosphoric acid,potassium citrate, potassium metaphosphate, monobasic potassiumphosphate, sodium acetate, sodium citrate, sodium lactate solution,dibasic sodium phosphate and monobasic sodium phosphate; chelating agentincluding edetate disodium and edetic acid; coating agent includingsodium carboxymethylcellulose, cellulose acetate, cellulose acetatephthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, methacrylic acid copolymer, methylcellulose, polyethyleneglycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide,carnauba wax, microcrystalline wax and zein; color including caramel,red, yellow, black and blends ferric oxide; complexing agent includingedetate disodium, edetic acid, gentisic acid ethanolamide andoxyquinoline sulfate; desiccant including calcium chloride, calciumsulfate and silicon dioxide; emulsifying and/or solubilizing agentincluding acacia, cholesterol, diethanolamine (adjunct), glycerylmonostearate, lanolin alcohols, lecithin, mono- and di-glycerides,monoethanolamine (adjunct), oleic acid (adjunct), oleyl alcohol(stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castoroil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether,polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, propylene glycoldiacetate, propylene glycol monostearate, sodium lauryl sulfate, sodiumstearate, sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan monostearate, stearic acid, trolamine andemulsifying wax; filtering aid including powdered cellulose and purifiedsiliceous earth; flavors and perfumes including anethole, benzaldehyde,ethyl vanillia, menthol, methyl salicylate, monosodium glutamate, orangeflower oil, peppermint, peppermint oil, peppermint spirit, rose oil,stronger rose water, thymol, tolu balsam tincture, vanilla, vanillatincture and vanillin; glidant and/or anticaking agent including calciumsilicate, magnesium silicate, colloidal silicon dioxide and talc;humectant including glycerin, hexylene glycol and propylene glycol,sorbitol; ointment base including lanolin, anhydrous lanolin,hydrophilic ointment, white ointment, yellow ointment, polyethyleneglycol ointment, petrolatum, hydrophilic petrolatum, white petrolatum,rose water ointment and squalene; plasticizer including castor oil,diacetylated monoglycerides, diethyl phthalate, glycerin, mono- anddi-acetylated monoglycerides, polyethylene glycol, propylene glycol,triacetin and triethyl citrate; polymer membrane including celluloseacetate; solvent including acetone, alcohol, diluted alcohol, amylenehydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride,chloroform, corn oil, cottonseed oil, ethyl acetate, glycerin, hexyleneglycol, isopropyl alcohol, methyl alcohol, methylene chloride, methylisobutyl ketone, mineral oil, peanut oil, polyethylene glycol, propylenecarbonate, propylene glycol, sesame oil, water for injection, sterilewater for injection, sterile water for irrigation and purified water;sorbent including powdered cellulose, charcoal and purified siliceousearth; sorbent, carbon dioxide including barium hydroxide lime and sodalime; stiffening agent including hydrogenated castor oil, cetostearylalcohol, cetyl alcohol, cetyl esters wax, hard fat, paraffin,polyethylene excipient, stearyl alcohol, emulsifying wax, white wax andyellow wax; suppository base including cocoa butter, hard fat andpolyethylene glycol; suspending and/or viscosity-increasing agentincluding acacia, agar, alginic acid, aluminum monostearate, bentonite,purified bentonite, bentonite magma, carbomer 934p,carboxymethylcelluloe calcium, carboxymethylcellulose sodium,carboxymethylcellulose sodium 12, carrageenan, cellulose,microcrystalline, and carboxy-methylcellulose sodium, dextrin, gelatin,guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, methylcellulose, pectin,polyethylene oxide, polyvinyl alcohol, povidone, propylene glycolalginate, silicon dioxide, colloidal silicon dioxide, sodium alginate,tragacanth and xanthan gum; sweetening agent including aspartame,dextrates, dextrose, dextrose excipient, fructose, mannitol, saccharin,saccharin calcium, saccharin sodium, sorbitol, sorbitol solution,sucrose, compressible sugar, confectioner's sugar and syrup; tabletbinder including acacia, alginic acid, sodium carboxymethylcellulose,microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquidglucose, guar gum, hydroxypropyl methylcellulose, methylcellulose,polyethylene oxide, povidone, pregelatinized starch and syrup; tabletand/or capsule diluent including calcium carbonate, dibasic calciumphosphate, tribasic calcium phosphate, calcium sulfate, microcrystallinecellulose, powdered cellulose, dextrates, dextrin, dextrose excipient,fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinizedstarch, sucrose, compressible sugar and confectioner's sugar; tabletdisintegrant including alginic acid, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, starch and pregelatinized starch; table and/or capsulelubricant including calcium stearate, glyceryl behenate, magnesiumstearate, mineral light oil, polyethylene glycol, sodium stearylfumarate, stearic acid, purified stearic acid, talc, hydrogenatedvegetable oil and zinc stearate; toxicity agent including dextrose,glycerin, mannitol, potassium chloride and sodium chloride; flavoredand/or sweetened vehicle including aromatic elixir, benzaldehyde elixircompound, iso-alcoholic elixir, peppermint water, sorbitol solution,syrup and tolu balsam syrup; oleaginous vehicle including almond oil,corn oil, cottonseed oil, ethyl oleate, isopropyl myristate, isopropylpalmitate, mineral oil, light mineral oil, myristyl alcohol,octyldodecanol, olive oil, peanut oil, persic oil, sesame oil, soybeanoil and squalene; solid carrier vehicle including sugar spheres; sterilevehicle including bacteriostatic sodium chloride injection andbacteriostatic water for injection; water repelling agent includingcyclomethicone, dimethicone and simethicone; wetting and/or solubilizingagent including benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docusate sodium, nonoxynol 9, nonoxynol 10,octoxynol 9, poloxamer, polyoxyl 35 castor oil, polyoxyl 40 hydrogenatedcastor oil, polyoxyl 50 stearate, polyoxyl 10 oleyl ether, polyoxyl 20cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, sodium lauryl sulfate, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate and tyloxapol. For example, the following inert ingredientscan be utilized singly or in various combinations; binders such asgelatin, polyvinylpyltolidone (PVP), pregelatinized starch, povidone,cellulose derivatives including methyl cellulose, carboxymethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose(HPC), sucrose and the like; diluents such as calcium carbonate,lactose, starch, microcrystalline cellulose, and the like; lubricantssuch as magnesium stearate, calcium stearate, zinc stearate, stearicacid, talc, hydrogenated vegetable oil and the like; glidants such assilicon dioxide, talc and the like; disintegrants such as alginic acid,methacrylic acid DVB, cross-linked PVP, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, starch, pregelatinized starch and the like; preferreddisintegrants are croscarmellose sodium, starch, pregelatinized starchand sodium starch glycolate with croscarmellose sodium being the mostpreferred disintegrant; sweetening agents, coloring agents; flavoringagents; antioxidants; and the like. The above inert ingredients can bepresent in amounts up to about 95% of the total composition weight.

A suitable combination of inert ingredients comprises microcrystallinecellulose, pregelatinized starch, gelatin, magnesium stearate, calciumcarbonate and sodium starch glycolate, in amounts of from about 20% toabout 85%, 5% to about 50%, 1% to about 15%, 0.05% to about 3%, 5% toabout 50%, and 1% to about 15%. A preferred combination of inertingredients is microcrystalline cellulose, pregelatinized starch,calcium carbonate, magnesium stearate and sodium starch glycolate inamounts of from about 20% to about 85%, 5% to about 50%, 5% to about50%, 0.05% to about 3%, and 1% to about 15%. Another preferredcombination of inert ingredients comprises: microcrystalline cellulose,pregelatinzed starch, magnesium stearate, and croscarmellose sodium inamounts of from about, 20% to about 85%, 5% to about 50%, 0.05 to about3%, 1% to about 10%. The most preferred combination of inert ingredientsis croscarmellose sodium, microcrystalline cellulose, lactose,pregelatinized starch and gelatin, in amounts of from about 1% to about10%, 20% to about 85%, 20% to about 85%, 1% to about 30% and 1% to about15% respectively. The most especially preferred combination of inertingredients is croscarmellose sodium, microcrystalline cellulose,lactose, pregelatinized starch, gelatin and magnesium stearate, inamounts of from about 1% to about 10%, 20% to about 85%, 20% to about85%, 1% to about 30%, 1% to about 15% and 0.05% to about 3%respectively. The following entries 1 through 7 in Table 5, provide themost preferred amounts of the respective inert ingredients which can beutilized in preparation of the tablet or capsule dosage forms.

TABLE 5 Preferred Amounts of Inert Ingredients Preferred #1 #2 #3 #4 #5#6 #7 Combination (%) (%) (%) (%) (%) (%) (%) Croscarmellose 4.8 4.8 — —4.8 6 — Sodium (4.6) Micro- 33.8 33.7 34.9 36.5 25.7 33.3 21.1crystalline (32.4) (33.5) (35.1) Cellulose Lactose 33.8 33.7 — — 25.7 —— (32.4) Pregelatinized 9.6 9.6 29.4 31.0 9.6 30 30 Starch (9.2) (28.3)(29.8) Gelatin 3.5 3.5 3.3 — 3.5 — — (3.4) (3.1) Magnesium — 0.5 0.5 0.50.75 0.75 0.75 Stearate (0.5) (0.5) (0.5) Calcium — — 15.6 15.6 — — 15.6Carbonate (15.0) (15.0) Sodium Starch — — 5.6 5.6 — — 10.0 Glycolate(5.4) (5.4)

The above entries in Table 5 represent percent by weight of thecomposition. The entries in parentheses for entries #2, #3, and #4represent the percent by weight of the composition after coating thetablet. It is understood by one of ordinary skill in the art that theabove combinations of inert ingredients, when combined with the chosenpiperidinoalkanol compound of formulas (I) through (IIIb), such as4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride or polymorphs, pseudomorphs or mixtures thereof, arethen manufactured in the chosen solid unit dosage form, such as acapsule or tablet, utilizing techniques well known in the art ofpharmaceutical science.

In general, solid unit dosage forms of the present invention can beformulated and manufactured in capsule 10 form using the followingprocedure:

The desired inert ingredients are blended together with thepiperidinoalkanol compound of formulas (I) through (IIIb) utilizingtechniques and procedures well known to one of ordinary skill in theart. For example, microcrystalline cellulose, lactose, pregelatinizedstarch and a piperidinoalkanol compound of formulas (I) through (IIIb),such as4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of greater than about 1m²/g, are blended together. A solution of gelatin in water is added andmixed in with the powder blend. The resulting wet granulation is thendried and milled to uniform size. Croscarmellose sodium is then added tothe milled granulation and blended to produce the final granulation.This granulation is then filled into hard gelatin capsules underconventional conditions as is well known to one of ordinary skill in theart.

In general, solid unit dosage forms of the present invention can beformulated and manufactured in tablet form using one of the followingprocedures:

The desired inert ingredients are blended together with thepiperidinoalkanol compound of formulas (I) through (IIIb) utilizingtechniques and procedures well known to one of ordinary skill in theart. For example, microcrystalline cellulose, lactose, pregelatinizedstarch and a piperidinoalkanol compound of formulas (I) through (IIIb),such as4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride or polymorphs, pseudomorphs or mixtures thereof, witha particle surface area of greater than about 1.0 m²/g, are blendedtogether. A solution of gelatin in water is added and mixed in with thepowder blend. The resulting wet granulation is then dried and milled touniform size. Croscarmellose sodium and magnesium stearate are thenadded to the milled granulation and blended to produce the finalgranulation. This granulation is then compressed into tablets underconventional conditions as is well known to one of ordinary skill in theart. The compressed tablets can be film coated using standardingredients and procedures commonly used and well known in the art ofpharmaceutical science.

In an additional general procedure, microcrystalline cellulose, thepregelatinized starch, part of the croscarmellose sodium and apiperidinoalkanol compounds of formulas (I) through (IIIb), such as4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride are blended together. Water is added and mixed withthe powder blend. The resulting wet granulation is then dried and milledto a uniform size. Additional microcrystalline cellulose andcroscarmellose sodium are added to the granulation and blended. Finally,magnesium stearate is added and blended with the mixture to produce thefinal granulation. This granulation is then compressed into tabletsunder conventional conditions well known to one of ordinary skill in theart. The compressed tablets can be film coated using standardingredients and procedures used and well known in the art ofpharmaceutical science.

Another example would include blending microcrystalline cellulose, thepregelatinized starch, the calcium carbonate, part of the sodium starchglycolate, and a compound of formulas (I) through (IIIb), such as4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride or polymorphs, pseudomorphs or mixtures thereof.Water is added and mixed with the powder blend. The resulting wetgranulation is then dried and milled to a uniform size. Additionalmicrocrystalline cellulose and the remaining sodium starch glycolate areblended together. The resulting mixture is blended with the magnesiumstearate to produce the final granulation. This granulation is thencompressed into tablets under conventional conditions well known to oneof ordinary skill in the art. The compressed tablets can be filmedcoated using standard ingredients and procedures used and well known inthe art of pharmaceutical science.

The above procedures may also be used for preparation of solid unitdosage forms wherein the piperidinoalkanol compound of formulas (I)through (IIIb), such as4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,dimethylbenzeneacetic acid hydrochloride or polymorphs, pseudomorphs ormixtures thereof, has a particle surface area less than about 1 m²/g.

For the entries 1 through 4 in Table 5, wherein the solid unit dosageform is a tablet, the quantity of compound of the formula;

wherein X is a number ranging from about zero to 5, and the individualoptical isomers thereof, dissolved in 45 minutes, is not less than 75%of label in water, at a temperature of about 37° C. and about 50 rpmwhen measured according to USP Apparatus 2 as is disclosed in the UnitedStates Pharmacopeia, 23, U.S. Pharmacopeial Convention, Inc., Rockville,Md., 20852 (1995), pages 1791-1793 which is hereby incorporated byreference.

For the entries 5 through 7 in Table 5, wherein the solid unit dosageform is a tablet, the quantity of compound of the formula;

wherein X is a number ranging from about zero to 5, and the individualoptical isomers thereof, dissolved in 45 minutes, is not less than 75%of label in 0.001 N aqueous hydrochloric acid, at a temperature of about37° C. and about 50 rpm when measured according to USP Apparatus 2 as isdisclosed in the United States Pharmacopeia, 23, U.S. PharmacopeialConvention, Inc., Rockville, Md., 20852 (1995), pages 1791-1793, whichis hereby incorporated by reference.

The following examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way. Thereagents and starting materials are available to one of ordinary skillin the art. As used herein, the following terms have the indicatedmeanings: “m²/g” refers to square meters per gram and is used as ameasurement of particle surface area; “kg” refers to kilograms; “g”refers to grams; “mmol” refers to millimoles; “ml” refers tomilliliters; “bp” refers to boiling point; “mp” refers to melting point;“° C.” refers to degrees Celsius; “° F.” refers to degrees Fahrenheit;“mm Hg” refers to millimeters of mercury; “μL” refers to micro-liters;and “μg” refers to micrograms.

EXAMPLE 1 20 mg Gelatin Capsules for Oral Administration

Combine 32.4 kg of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g, 76.1kg microcrystalline cellulose, 76.1 kg lactose, and 21.6 kgpregelatinized starch and blend in a mixer for 5 minutes. To thismixture, add a solution of 7.9 kg of gelatin in 55.0 kg purified water(prepared by adding the gelatin to the water and heating the dispersionwith mixing until solution of the gelatin is attained) and continuemixing until a good granulation is formed. Pass the granulation througha 0.375 inch screen and dry at 60° C. until a moisture content of lessthan 3.0% is achieved as determined by a Computrac moisture balance at125° C. Mill the dried granulation through a 0.065 inch screen. To thegranulation add 10.8 kg of croscarmellose sodium and mix for about 10minutes. Fill the granulation into size 3 hard gelatin capsules to afill weight of 138.9 mg granulation per capsule. This procedure resultsin about 1,620,000 capsules of the composition shown in table 6 below.

TABLE 6 Composition of 20 mg Gelatin Capsules. AMOUNT COMPOSITIONINGREDIENT mg/capsule % by weight Piperidinoalkanol Compound* 20.0 14.4Microcrystalline Cellulose 47.0 33.8 Lactose 47.0 33.8 PregelatinizedStarch 13.3 9.6 Croscarmellose Sodium 6.7 4.8 Gelatin 4.9 3.5*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 2 30 mg Capsules for Oral Administration

Combine 144.0 g of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g, 338.5g microcrystalline cellulose, 338.5 g lactose, and 96.0 g pregelatinizedstarch in a blender and blend. To the powder blend, add a solution of35.0 g of gelatin in 286.1 g of purified water (prepared by adding thegelatin to the water and heating the dispersion with mixing untilsolution of the gelatin is attained) and continue mixing until a goodgranulation is formed. Pass the granulation through a screen, ifnecessary, and dry the granulation. Mill the dried granulation. To themilled granulation in a blender, add 48.0 g of croscarmellose sodium andblend. Fill the finished granulation into size 1 hard gelatin capsulesto the desired weight. This procedure results in 4801 capsules each witha total fill weight of 208.3 mg with the composition shown in table 7below.

TABLE 7 Composition of 30 mg Capsules. AMOUNT COMPOSITION INGREDIENTmg/capsule % by weight Piperidinoalkanol Compound* 30.0 14.4Microcrystalline Cellulose 70.5 33.8 Lactose 70.5 33.8 PregelatinizedStarch 20.0 9.6 Gelatin 7.3 3.5 Croscarmellose Sodium 10.0 4.8*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 3 30 mg Capsules for Oral Administration

Combine 144.1 g of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g, 338.5g microcrystalline cellulose, 338.5 g lactose, and 96.0 g pregelatinizedstarch in a blender and blend. To the powder blend, add a solution of35.1 g of gelatin in 286.2 g of purified water (prepared by adding thegelatin to the water and heating the dispersion with mixing untilsolution of the gelatin is attained) and continue mixing until a goodgranulation is formed. Pass the granulation through a screen, ifnecessary, and dry the granulation. Mill the dried granulation. To themilled granulation in a blender, add 48.0 g of croscarmellose sodium andblend. Add 4.8 g of magnesium stearate to the blend and blend further.Fill the finished granulation into size 1 hard gelatin capsules to thedesired weight. This procedure results in 4802 capsules each with atotal fill weight of 209.3 mg with the composition shown in table 8below.

TABLE 8 Composition of 30 mg Capsules. AMOUNT COMPOSITION INGREDIENTmg/capsule % by weight Piperidinoalkanol Compound* 30.0 14.3Microcrystalline Cellulose 70.5 33.7 Lactose 70.5 33.7 PregelatinizedStarch 20.0 9.6 Gelatin 7.3 3.5 Croscarmellose Sodium 10.0 4.8 MagnesiumStearate 1.0 0.5*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 4 40 mg Gelatin Capsules for Oral Administration

Combine 32.4 kg of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 24 m²/g, 76.1kg microcrystalline cellulose, 76.1 kg lactose, and 21.6 kgpregelatinized starch and blend in a mixer for 5 minutes. To thismixture, add a solution of 7.9 kg of gelatin in 55.0 kg purified water(prepared by adding the gelatin to the water and heating the dispersionwith mixing until solution of the gelatin is attained) and continuemixing until a good granulation is formed. Pass the granulation througha 0.375 inch screen and dry at 60° C. until a moisture content of lessthan 3.0% is achieved as determined by a Computrac moisture balance at125° C. Mill the dried granulation through a 0.065 inch screen. To thegranulation add 10.8 kg of croscarmellose sodium and mix for about 10minutes. Fill the granulation into size 1 hard gelatin capsules to atotal fill weight of 277.8 mg granulation per capsule. This procedureresults in about 810,000 capsules of the composition shown in table 9below.

TABLE 9 Composition of 40 mg Gelatin Capsules. AMOUNT COMPOSITIONINGREDIENT mg/capsule % by weight Piperidinoalkanol Compound* 40.0 14.4Microcrystalline Cellulose 94.0 33.8 Lactose 94.0 33.8 PregelatinizedStarch 26.6 9.6 Croscarmellose Sodium 13.3 4.8 Gelatin 9.8 3.5*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride 20 with a particle surface area of about 2-4 m²/g.

EXAMPLE 5 60 mg Gelatin Capsules for Oral Administration

Combine 32.4 kg of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g, 76.1kg microcrystalline cellulose, 76.1 kg lactose, and 21.6 kgpregelatinized starch and blend in a mixer for 5 minutes. To thismixture, add a solution of 7.9 kg of gelatin in 55.0 kg purified water(prepared by adding the gelatin to the water and heating the dispersionwith mixing until solution of the gelatin is attained) and continuemixing until a good granulation is formed. Pass the granulation througha 0.375 inch screen and dry at 60° C. until a moisture content of lessthan 3.0% is achieved as determined by a Computrac moisture balance at125° C. Mill the dried granulation through a 0.065 inch screen. To thegranulation add 10.8 kg of croscarmellose sodium and mix for about 10minutes. Fill the granulation into size 0 hard gelatin capsules to atotal fill weight of 416.7 mg granulation per capsule. This procedureresults in about 540,000 capsules of the composition shown in table 10below.

TABLE 10 Composition of 60 mg Capsules. AMOUNT COMPOSITION INGREDIENTmg/capsule % by weight Piperidinoalkanol Compound* 60.0 14.4Microcrystalline Cellulose 141.0 33.8 Lactose 141.0 33.8 PregelatinizedStarch 40.0 9.6 Croscarmellose Sodium 20.0 4.8 Gelatin 14.7 3.5*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 6 30 mg Tablets for Oral Administration

Combine 144.1 g of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g, 338.5g microcrystalline cellulose, 338.5 g lactose, and 96.0 g pregelatinizedstarch and blend in a mixer for 5 minutes. To the powder blend, add asolution of 35.1 g of gelatin in 286.2 g purified water (prepared byadding the gelatin to the water and heating the dispersion with mixinguntil solution of the gelatin is attained) and continue mixing until agood granulation is formed. Pass the granulation through a screen, ifnecessary and dry the granulation. Mill the dried granulation, add 48.0g of croscarmellose sodium and mix in a blender. Then add 4.8 g ofmagnesium stearate to the blender and blend further. Compress thefinished granulation into tablets. Place the tablets into a coating panand coat the tablets with a dispersion of 30.3 g of Opadry YS-1-18027-A(Colorcon, West Point Pa.) in 138.0 g of water and a dispersion of 10.6g of Opadry YS-1-19016 (Colorcon, West Point Pa.) in 121.9 g of water.This procedure results in 4802 tablets each with a total weight of 217.8mg with the composition shown in table 11 below. The percentages inparentheses in table 11 represent the percent by weight of thecomposition after coating the tablet.

TABLE 11 Composition of 30 mg Tablets. AMOUNT COMPOSITION INGREDIENTmg/tablet % by weight Piperidinoalkanol Compound* 30.0 14.3 (13.8)Microcrystalline Cellulose 70.5 33.7 (32.4) Lactose 70.5 33.7 (32.4)Pregelatinized Starch 20.0 9.6 (9.2) Croscarmellose Sodium 10.0 4.8(4.6) Gelatin 7.3 3.5 (3.4) Magnesium Stearate 1.0 0.5 (0.5) OpadryYS-1-18027-A 6.3  — (2.9) Opadry YS-1-19016 2.2  — (1.0)*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 7 30 mg Tablets for Oral Administration

Combine 149.9 g of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g, 214.2g microcrystalline cellulose, 218.7 g calcium carbonate, and 411.6 gpregelatinized starch in a blender and blend. To the powder blend, add asolution of 45.5 g of gelatin in 400.0 g of purified water (prepared byadding the gelatin to the water and heating the dispersion with mixinguntil solution of the gelatin is attained) and continue mixing until agood granulation is formed. Pass the granulation through a screen, ifnecessary, and dry the granulation. Screen the remainingmicrocrystalline cellulose and add the 274.1 g of microcrystallinecellulose with 78.3 g sodium starch glycolate to the dried granulationin a blender and blend. Screen the magnesium stearate and add the 7.5 gof magnesium stearate to the blend and blend further. Compress thefinished granulation into tablets. Place the tablets into a coating panand coat the tablets with a dispersion of 42.0 g of Opadry YS-1-18027-A(Colorcon, West Point Pa.) in 191.0 g of water and a dispersion of 14.5g of Opadry YS-1-19016 (Colorcon, West Point Pa.) in 166.8 g of water.This procedure results in 4999 tablets each with a total weight of 291.3mg with the composition shown in table 12 below. The percentages inparentheses in table 12 represent the percent by weight of thecomposition after coating the tablet.

TABLE 12 Composition of 30 mg Tablets. AMOUNT COMPOSITION INGREDIENTmg/tablet % by weight Piperidinoalkanol Compound* 30.0 10.7 (10.3)Microcrystalline Cellulose 97.7 34.9 (33.5) Calcium Carbonate 43.7 15.6(15.0) Pregelatinized Starch 82.3 29.4 (28.3) Gelatin 9.1 3.3 (3.1)Sodium Starch Glycolate 15.7 5.6 (5.4) Magnesium Stearate 1.5 0.5 (0.5)Opadry YS-1-18027-A 8.4  — (2.9) Opadry YS-1-19016 2.9  — (1.0)*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 8 30 mg Tablets for Oral Administration

Combine 149.9 g of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g, 214.2g microcrystalline cellulose, 218.7 g calcium carbonate, and 434.3 gpregelatinized starch in a blender and blend. To the powder blend, add460.0 g of purified water and blend until a good granulation is formed.Pass the granulation through a screen, if necessary, and dry thegranulation. Screen the remaining microcrystalline cellulose and add the296.8 g of microcrystalline cellulose with 78.3 g sodium starchglycolate to the dried granulation in a blender and blend. Screen themagnesium stearate and add the 7.5 g of magnesium stearate to the blendand blend further. Compress the finished granulation into tablets. Placethe tablets into a coating pan and coat the tablets with a dispersion of42.0 g of Opadry YS-1-18027-A (Colorcon, West Point Pa.) in 191.3 g ofwater and a dispersion of 14.5 g of Opadry YS-1-19016 (Colorcon, WestPoint Pa.) in 166.8 g water. This procedure results in 4999 tablets eachwith a total weight of 291.3 mg with the composition shown in table 13below. The percentages in parentheses in table 13 represent the percentby weight of the composition after coating the tablet.

TABLE 13 Composition of 30 mg Tablets. AMOUNT COMPOSITION INGREDIENTmg/tablet % by weight Piperidinoalkanol Compound* 30.0 10.7 (10.3)Microcrystalline Cellulose 102.2 36.5 (35.1) Calcium Carbonate 43.7 15.6(15.0) Pregelatinized Starch 86.9 31.0 (29.8) Sodium Starch Glycolate15.7 5.6 (5.4) Magnesium Stearate 1.5 0.5 (0.5) Opadry YS-1-18027-A 8.4 — (2.9) Opadry YS-1-19016 2.9  — (1.0)*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 9

In a manner analogous to the procedures described in examples 1 through8, the respective tablets and capsules can be prepared utilizing4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2 m²/g to about6 m²/g.

EXAMPLE 10

In a manner analogous to the procedures described in examples 1 through8, the respective tablets and capsules can be prepared utilizing4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2 m²/g to about10 m²/g.

EXAMPLE 11

In a manner analogous to the procedures described in examples 1 through8, the respective tablets and capsules can be prepared utilizing4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area greater than about 1m²/g.

EXAMPLE 12

In a manner analogous to the procedures described in examples 1 through8, the respective tablets and capsules can be prepared utilizing4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which has not been subjected to micronization suchthat the4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride has a particle surface area of less than about 1.0m²/g.

EXAMPLE 13

Utilizing the procedures described in examples 1 through 12, the tabletsand capsules may contain4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-,dimethylbenzeneacetic acid hydrochloride in amounts from about 5 mg toabout 120 mg. The4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride and inert ingredients are present in the describedpercentage amounts by weight, which are readily determined by one ofordinary skill in the art from the previous examples. For example, oneof ordinary skill in the art, following the procedures of examples 1through 12 in an analogous manner, can prepare tablets and capsules, inaddition to those already set forth, wherein4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride is present in amounts of 10 mg, 20 mg, 30 mg, 40 mg,50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg and 120 mg.

EXAMPLE 14 180 mg Tablet for Oral Administration

Combine 180.0 g of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride, 78.0 g of microcrystalline cellulose (Avicel PH101)180.0 g of pregelatinized starch, and part of the 36.0 g of the sodiumcroscarmellose in a blender and blend. To the powder blend, add 180 g ofpurified water and mix. Dry the resulting wet granulation. Screen thedried granulation through a 20 mesh screen. Transfer the granulation toa blender and add 121.5 g of microcrystalline cellulose (Avicel PH102)and the remaining amount of the Sodium Croscarmellose. Blend thesecomponents. Add 4.5 g of magnesium stearate and blend. Compress thefinished granulation into tablets. Table 14 provides the composition ofeach tablet in percent by weight prior to coating the tablet.

To coat the compressed tablets with a peach aqueous coating, prepare anaqueous suspension comprised of 2.84 g of hydroxypropyl methyl cellulose(USP2910 E-15), 1.89 g of hydroxypropyl methyl cellulose (USP2910E-5)0.51 g of Povidone (USP), 2.02 g of titanium dioxide (USP), 0.025 g ofpink iron oxide blend, 0.04 g of yellow iron oxide blend, 0.73 g ofsilicone dioxide (M7) 3.94 g of polyethylene glycol 400 (N.F.), andabout 88 g of purified water. Place the tablets into a coating pan andcoat the tablets using the peach aqueous suspension to achieve about a3% weight gain. This procedure provides a tablet with a total weight of618.0 mg.

TABLE 14 Composition of 180 mg Tablets. Amount Composition INGREDIENTmg/tablet % Weight Piperidinoalkanol Compound* 180.0 30.0Microcrystalline Cellulose 199.5 33.3 Pregelatinized Starch 180.0 30.0Croscarmellose Sodium 36.0 6.0 Magnesium Stearate 4.5 0.75*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 15 180 mg Tablet for Oral Administration

Combine 180.0 g of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride, 84.5 g of microcrystalline cellulose (Avicel PH101),240 g of pregelatinzed starch, 125.0 g of calcium carbonate (Heavy), andpart of the 80.0 g of the Sodium starch glycolate in a blender andblend. To the powder mix, add 224 g of water and mix. Dry the resultingwet granulation. Screen the dried granulation through a 20 mesh screen.Transfer the granulation to a blender. Add 84.5 g of microcrystallinecellulose (Avicel PH102) and the remaining amount of the sodium starchglycolate. Blend these components. Add 6.0 g of magnesium stearate andblend. Compress the finished granulation into Tablets. Table 15 providesthe composition of each tablet in percent by weight prior to coating thetablet.

To coat the compressed tablets with a white aqueous coating, prepare anaqueous suspension comprised of 2.84 g of hydroxypropyl methyl cellulose(USP2910 E-15), 1.89 g of hydroxypropyl methyl cellulose (USP2910E-5)0.51 g of Povidone (USP), 2.1 g of titanium dioxide (USP), 0.73 g ofsilicone dioxide (M7) 3.94 g of polyethylene glycol 400 (N.F.), andabout 88 g of purified water. Place the tablets into a coating pan andcoat the tablets using the white aqueous suspension to achieve about a3% weight gain. This procedure provides a tablet with a total weight of824.0 mg.

TABLE 15 Composition of 180 mg Tablets. Amount Composition INGREDIENTmg/tablet % weight Piperidinoalkanol Compound* 180.0 mg 22.5Microcrystalline Cellulose 169.0 21.1 Pregelatinized Starch 240.0 30.0Sodium Starch glycolate 80.0 10.0 Calcium Carbonate 125.0 15.6 MagnesiumStearate Special 6.0 0.75*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 16 180 mg Tablet for Oral Administration

Combine 180.0 g of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride, 154.0 g of microcrystalline cellulose (AvicelPH101), 57.5 g of pregelatinized starch, and 154 g of lactose (hydrous,Fast-Flo) in a blender and blend. Prepare a granulating liquid by adding21.2 g of gelatin to 142 g of water and heating the dispersion.

Add the granulating liquid to the powder blend and mix. Dry theresulting wet granulation. Screen the dried granulation through a 20mesh screen. Transfer the granulation to a blender. Add 28.8 g of SodiumCroscarmellose to the granulation and blend. Add 4.5 g of magnesiumstearate to the granulation and blend. Compress the finished granulationinto tablets. Table 16 provides the composition of each tablet inpercent by weight prior to coating the tablet.

The finished tablets may be coated in a manner analogous to thosedescribed in example 14 with the peach aqueous coating or in example 15with the white aqueous coating.

TABLE 16 Composition of 180 mg Tablets. Amount Composition INGREDIENTmg/tablet % Weight Piperidinoalkanol Compound* 180.0 30.0Microcrystalline Cellulose 154 25.7 pregelatinzed starch 57.5 9.6Lactose 154.0 25.7 Gelatin 21.2 3.5 Sodium Croscarmellose 28.8 4.8Magnesium Stearate 4.5 0.75*4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 17 60 mg Tablets for Oral Administration

Combine 60 g of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride 141.0 g of microcrystalline cellulose, 141.0 glactose, and 40 g pregelatinized starch and blend in a mixer. To thismixture, add a solution of 14.7 g of gelatin in 101.9 g purified water(prepared by adding the gelatin to the water and heating the dispersionwith mixing until solution of the gelatin is attained) and continuemixing until a granulation is formed. Pass the granulation through ascreen and dry. To the granulation add 20.0 g of croscarmellose sodiumand mix. Then add 2.1 g of magnesium stearate to the blend and blendfurther. Compress the finished granulation into tablets. Table 17provides the composition of each tablet in percent by weight prior tocoating the tablet.

The resulting tablets may be coated in a manner analogous to thatdescribed in example 6 with Opadry YS-1-18027-A and Opadry YS-1-19016.Alternatively, the resulting tablets may be coated in a manner analogousto that described in example 14 with the peach aqueous coating or inexample 15 with the white aqueous coating.

TABLE 17 Composition of 60 mg Tablets. Amount Composition INGREDIENTmg/tablet % Weight Piperidinoalkanol Compund* 60.0 14.3 MicrocrystallineCellulose 141.0 33.7 Lactose 141.0 33.7 Pregelatinized Starch 40.0 9.6Sodium Croscarmellose 20.0 4.8 Gelatin 14.7 3.5 Magnesium Stearate 2.10.5*4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybuyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2-4 m²/g.

EXAMPLE 18

In a manner analogous to the procedures described in examples 14 through17, the tablets can be prepared utilizing4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2 m²/g to about6 m²/g.

EXAMPLE 19

In a manner analogous to the procedures described in examples 14 through17, the tablets can be prepared utilizing4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area of about 2 m²/g to about10 m²/g.

EXAMPLE 20

In a manner analogous to the procedures described in examples 14 through17, the tablets can be prepared utilizing4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride with a particle surface area greater than about 1m²/g.

EXAMPLE 21

In a manner analogous to the procedures described in examples 14 through17, the respective tablets and capsules can be prepared utilizing4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride which has not been subjected to micronization suchthat the4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride has a particle surface area of less than about 1.0m²/g.

The following examples present typical processes for preparing theanhydrous and hydrated, pharmaceutically acceptable acid addition saltsof the piperidinoalkanol compounds of the formulas (III) and (IIIa),polymorphs and pseudomorphs thereof. These examples are understood to beillustrative only and are not intended to limit the scope of the presentinvention in any way.

Differential Scanning Calorimetry analysis were performed using a TA2910 DSC with open aluminum pans. The samples were heated to 240° C. at5° C./minute with a 50 mL/minute nitrogen purge.

X-Ray Powder Diffraction analyses were performed as follows:

The samples were loaded into a quartz (zero scatter) sample holder forthe XRPD pattern measurement. The XRPD patterns were measured using apowder diffractometer equipped with a Co X-ray tube source, primary beammonochromator, and position sensitive detector (PSD). The incident beamwas collimated using a 1° divergence slit. The active area on the PSDsubtended approximately 5°2θ. The source was operated at 35 kV and 30 mAand the sample was illuminated with Co Kα₁ radiation. XRPD data werecollected from 5 to 55° 2θ at a rate of 0.25°2θ/minute and a step widthof 0.02°2θ. The XRPD patterns were measured without the addition of aninternal calibrant.

Peak positions and intensities for the most prominent features weremeasured using a double-derivative peak picking method. X-ray peaks withI/I_(o) greater than 20% were reported. The cutoff was chosenarbitrarily. The intensities are rounded to the nearest 5%. Certainpeaks appear sensitive to preferred orientation that is caused bychanges in crystallite morphology. This results in large changes in theI/I_(o) value.

EXAMPLE 22 Preparation of Form II4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride Method A

Mix ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride (101.92 g, 0.1807 mol) and methanol (510 mL) and stir.Rapidly add 50% sodium hydroxide (72.27 g, 0.903 mol) and wash in withwater (61 mL). Heat to reflux for 2 hours, allow to cool to 35° C. andtreat with sodium borohydride (3.42 g, 0.0903 mol). Add water (100 mL)and maintain at 35° C. for 10 hours. Add 37% hydrochloric acid (53.0 g)to adjust pH to 11.5. Add acetone (26.5 mL) and water (102 mL). Hold at35° C. for 2 hours and adjust to pH 2.5 with 37% hydrochloric acid(44.69 g). Dilute with water (408 mL), cool to −15° C., stir for 1.5hours and collect the precipitate by vacuum filtration. Wash thefiltercake with deionized water (3×100 mL) and vacuum dry to give4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (97.10 g).

Method B

Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate,hydrochloride (60.01 g, 0.106 mol) in a 1-L three necked round-bottomflask and fit the flask with a mechanical stirrer, a Claisen head, athermometer and a reflux condenser with a nitrogen bubbler on top. Addmethanol (300 mL) and turn the stirrer on. Dilute the slurry with water(60 mL) and heat to 52-54° C. over 15-20 minutes. Hold at 52° C. for 2hours and then add 20 50% sodium hydroxide (42.54 g, 0.532 mol). Heat at73° C. for approximately 1 hour, 45 minutes, cool to less than 35° C.using a water bath and then add sodium borohydride (2.02 g, 0.0534 mol).Stir overnight at 35° C., treat with acetone (15.5 mL) and stir for 2hours at 35° C. Acidify the mixture to a pH of 1.85 with 28%hydrochloric acid (75.72 g), dilute with water (282 mL), stir for about30 minutes and cool over about 2 hours to −15° C. Filter the solids offand wash with water (2×75 mL) and ethyl acetate (2×75 mL). Vacuum drythe solid and allow to stand for 2 days to give4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (57.97 g, 91.5%) as a fine powder.

Method C

Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate(56.12 g, 0.1064 mol) in a 1-L three necked round-bottom flask and fitthe flask with a mechanical stirrer, a Claisen head, a thermometer and areflux condenser with a nitrogen bubbler on top. Add methanol (300 mL)and turn the stirrer on. Dilute the slurry with water (60 mL) and heatto reflux using a heating mantle controlled by a Therm-O-Watch. When themixture reaches about 35° C., treat with 50% sodium hydroxide (34.05 g,0.4256 mol) and rinse in with water (42 mL). Stir at reflux for 2 hours,15 minutes, cool over 1 hour to 35° C. and then treat with sodiumborohydride (2.02 g, 0.0534 mol). Stir for 7.5 hours and allow to standat room temperature without stirring for 1.75 days. Warm the mixture to35° C. and quench with acetone (15.5 mL, 0.21 mol) and stir for 2 hours.Add water (60 mL) and adjust the pH to 2.5 with 32% hydrochloric acid(65.22 g). Cool to 40° C. and rinse the pH probe with water (25 mL). Addwater over about 30 minutes (192 mL), hold the temperature at 33° C. for10 minutes and add a few seed crystals. Cool the slurry to −12° C. overabout 45 minutes and isolate the solid by filtration (586.2 g). Washwith water (2×100 mL) and then with ethyl acetate (100 mL, prechilled toabout −10° C.). Vacuum dry overnight (1 mmHg, 50° C.) to give4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (58.86 g, 98%) as a white solid.

EXAMPLE 23 Preparation of Form IV4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-aza-dimethylbenzeneaceticacid hydrochloride (Form IV)

Place ethyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate(56.12 g, 0.1064 mol) in a 1-L three necked round-bottom flask and fitthe flask with a mechanical stirrer, a Claisen head, a thermometer and areflux condenser with a nitrogen bubbler on top. Add methanol (300 mL)and turn the stirrer on. Dilute the slurry with water (60 mL) and heatto reflux using a heating mantle controlled by a Therm-O-Watch. When themixture reaches about 35° C., treat with 50% sodium hydroxide (34.05 g,0.4256 mol) and rinse in with water (42 mL). Stir at reflux for 2 hours,15 minutes, cool over 1 hour to 35° C. and then treat with sodiumborohydride (2.02 g, 0.0534 mol). Stir for 7.5 hours and allow to standat room temperature without stirring for 1.75 days. Warm the mixture to35° C. and quench with acetone (15.5 mL, 0.21 mol) and stir for 2 hours.Add water (60 mL) and adjust the pH to 2.5 with 32% hydrochloric acid(65.22 g). Cool to 40° C. and rinse the pH probe with water (25 mL).Hold the temperature at 33° C. for 10 minutes, add a few seed crystalsand add water over about 4 hours (192 mL) at 35° C. Cool the slurry to−12° C. over about 45 minutes and isolate the solid by filtration (586.2g). Wash with water (2×100 mL) and then with ethyl acetate (100 mL,prechilled to about −10° C.). Vacuum dry overnight (1 mmHg, 50° C.) togive4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV); mp 115-116° C. (dec).

XRPD: Table 18

TABLE 18 D-Space, Intensity, Angstroms I/I_(o), % 10.38 60 6.97 45 6.4150 5.55 30 5.32 100 5.23 55 5.11 35 4.98 25 4.64 30 4.32 35 4.28 75 4.1250 4.02 45 3.83 60 3.65 20 3.51 55 3.46 25 2.83 20

EXAMPLE 24 Conversion of Form II to Form I4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I)

Treat4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (20.0 g, 0.0355 mol) with deionizedwater (2 g) and add acetone (60 mL) in small portions over severalminutes with stirring. Filter through filter aid and wash the filtercake with acetone (30 mL). Wash the filtercake with acetone (22 mL),reflux filtrate and then slowly add ethyl acetate (32 mL over 15minutes) keeping the mixture at eflux. Reflux for 10 minutes, thenslowly add additional ethyl acetate (23 mL over 10 minutes) and refluxfor an additional 15 minutes. Add additional ethyl acetate (60 mL over5-10 minutes) and continue refluxing for 15 minutes. Cool toapproximately 8° C. in an ice bath, filter the solid and wash with ethylacetate (85 mL). Vacuum dry at 55° C. for 1.5 hours to give the titlecompound (18.16 g, 95%).

EXAMPLE 25 Conversion of Form II to Form I4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride Method A:

Treat4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (5.00 g, 0.0083 mol) withmethylethyl ketone (130 mL). Slowly add water (0.4 mL), filter throughfilter aid and wash the filter cake with methylethyl ketone (20 mL).Heat to reflux and distill off 75 mL of solvent, cool to −15° C. andcollect by vacuum filtration. Wash with methylethyl ketone (2×10 mL) andvacuum dry at 60° C. to give the title compound (4.33 g, 97%); mp196-198° C.

Method B:

Treat4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (1.4 g) with acetone (60 mL) andheat to reflux. Reduce the volume to approximately 35 mL to remove allwater which boils off as an azeotrope (88/12:acetone/water). Cool thesolution and collect the title compound as a crystalline solid.

Method C:

Mix4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (53.88 g, 0.100 mol) and add water(4.79 g) and methyl ethyl ketone (240 mL). Stir until the solid isslurried up and add additional methyl ethyl ketone (1 L). Stir for 0.5hours, filter through a pad of filter aid, wash the filtercake withmethyl ethyl ketone (100 mL) and transfer the filtrate and wash to a 2L, 3-necked flask fitted with a thermometer, mechanical stirrer anddistillation head. Distill off a total of 721 mL of methyl ethyl ketone,cool and stir over 1 hour to 40° C. Cool to −15° C. and hold for 10minutes. Collect the solid by vacuum filtration and wash the filtercakewith methyl ethyl ketone (2×65 mL) and vacuum dry at 55° C. overnight togive the title compound (52.76 g, 97.9%); mp 197.5-200° C.

Method D:

Treat4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (40.0 g, 0.0696 mol, assayed at93.6% purity, having 0.89 g water present and 35.1 g, 0.0575 mol,assayed at 88.0% purity, having 2.47 g water present) with water (8.30g; the amount calculated to bring the weight of water present to 17% ofthe anhydrous weight of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate, taking into account the water in thehydrated salt). Add methyl ethyl ketone (approximately 500 mL) and stiruntil most of the solids dissolve. Add additional methyl ethyl ketone(700 mL) in portions over approximately 10 minutes and continue stirringfor ½ hour. Filter through a thin pad of filter aid, wash the filtercakeand flask with additional methyl ethyl ketone (100 mL) and transfer to aboiling flask fitted with a thermometer, mechanical stirrer, heatingmantle, a 12-plate Oldershaw (vacuum-jacketed) distillation column and adistillation head with the capability of regulating the reflux ratio ina rough fashion, washing in with additional methyl ethyl ketone (100mL). Distill off 450 mL of solvent, cool to −15° C. and filter thesolid. Wash with methyl ethyl ketone (2×100 mL) and dry to give thetitle compound (68.3 g, 99.9%); mp 197-199° C.

Method E

Bring methyl ethyl ketone (4 mL) to a boil and add4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (500 mg). Decant the top layer and add methyl ethylketone (3 mL) to the aqueous layer. Boil the solution until thetemperature reached 79° C., reduce the volume by 25%, remove from heatand cover with aluminum foil. Allow the solution to cool, filter theresulting crystals and air dry to give the title compound.

EXAMPLE 26 Conversion of Form I to Form II4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate Method A

Treat4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) (2.0 g) with ethanol (4 mL) and deionizedwater (20 mL). Heat at 80° C. until a solution is formed and then stirat room temperature for 23 hours. Filter the resulting slurry, wash withwater (2×10 mL) and dry under vacuum at 35° C. overnight to give thetitle compound (1.88 g); mp 100-105° C.

XRPD: Table 19

TABLE 19 D-Space, Intensity, Angstroms I/I_(o), % 11.41 20 7.98 20 7.8345 6.58 45 6.42 60 5.66 20 5.52 45 5.39 30 5.23 65 5.14 45 4.86 65 4.72100 4.45 65 4.40 45 4.32 45 4.18 45 4.06 65 4.02 55 3.85 25 3.79 75 3.7495 3.61 80 3.56 25 3.47 65 3.41 20 2.74 20

Method B

Mix water (35.5 mL), methanol (26.3 mL) and sodium chloride (2.59 g).Add4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I) (4.77 g). Heat to reflux on a steam bathuntil dissolution and cool to −10° C. Filter the resulting solid, washwith water (2×25 mL) and vacuum dry overnight to give the title compound(4.80 g).

EXAMPLE 27 Conversion of Form II into Form III4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III)

Place4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form II) (55.56 g, 0.0929 mol having 10%water) in a pressure bottle along with water (2.96 g) and acetone (38.1g). Seal the bottle tightly and heat to approximately 80° C. Cool toabout 50° C., filter through filter aid in a coarse sintered glassfunnel and dilute with acetone (90 g). Transfer to a 1 L flask fittedwith a mechanical stirrer, thermometer and a reflux condenser. Heat themixture to reflux and allow to cool and stir over the weekend. Cool to−15° C. and filter on a coarse sintered glass funnel, wash with ethylacetate (2×50 mL) and vacuum dry at 50° C. Place a majority of the solidobtained (45.24 g) in a 500 mL three necked flask fitted with amechanical stirrer, thermometer and a reflux condenser. Add acetone (240mL) and water (4.82 g) and reflux the mixture overnight. Allow theslurry to cool to 35° C. and place in an ice water bath and cool to lessthen 5° C. Filter the solid off on a coarse sintered glass funnel, washwith ethyl acetate (50 mL) and vacuum dry at 50° C. for several hours togive the title compound as a white crystalline powder (43.83 g, 97%); mp166.5-170.5° C.

TABLE 20 Intensity, Angstroms I/I_(o), % 8.95 95 4.99 20 4.88 100 4.7535 4.57 25 4.47 25 4.46 20 3.67 20 3.65 25

EXAMPLE 28 Conversion of Form III into Form I4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I)

Place4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form III) (40.0 g as an ethyl acetate wetcake-27.9 gdry basis) in a 1 L three necked flask fitted with a mechanical stirrer,thermometer and a reflux condenser. Add acetone (240 mL) and heat themixture to reflux for about 20 hours. Cool the slurry to −15° C. andisolate the solids by filtration on a coarse sintered glass frit funnel.Wash with ethyl acetate (50 mL) and vacuum dry overnight to give thetitle compound (26.1 g, 93.7%); mp 197.5-199.5° C.

XRPD: Table 21

TABLE 21 D-Space, Intensity, Angstroms I/I_(o), % 11.75 35 7.23 35 6.2460 5.89 40 5.02 20 4.94 30 4.83 100 4.44 30 3.93 75 3.83 20 3.77 85 3.7125 3.62 30 3.32 25 3.31 20

EXAMPLE 29 Conversion of Form TV into Form I4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride (Form I)

Place4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV) (54.35 g, 0.0970 mol, having 4%water present) in a pressure bottle along with water (4.16 g) andacetone (38.1 g). Seal the bottle tightly and heat to approximately 80°C. Cool to less then 60° C., filter through filter aid in a coarsesintered glass funnel and rinse the filter cake with acetone (32.4 g).Place acetone (215 g) in a 1 L three necked flask fitted with amechanical stirrer, thermometer, a reflux condenser and containing asmall amount of Form I crystals and heat to reflux. Add a portion of theacetone/water solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV) (47.65 g) to the refluxing acetoneover about 10 minutes. Slowly add ethyl acetate (157.5 g) over 45minutes then add the remaining portion of the acetone/water solution of4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (Form IV), rinsed in with about 20 mL ofacetone. Add additional ethyl acetate (157.5 g) over 45 minutes to 1hour, maintaining the slurry at reflux. Stir for 15 minutes, cool to−15° C. and vacuum filter the white solid on a 350 μL coarse sinteredglass funnel. Wash the solids with ethyl acetate (2×50 mL) and vacuumdry overnight to give the title compound (50.36 g, 97%); mp 198-199.5°C.

XRPD: Table 22

TABLE 22 D-Space, Intensity, Angstroms I/I_(o), % 14.89 20 11.85 20 7.3020 6.28 70 5.91 25 5.55 20 5.05 25 4.96 55 4.85 100 4.57 45 4.45 55 3.9445 3.89 20 3.84 20 3.78 60 3.72 35 3.63 20 3.07 20 3.04 20 2.45 20

Utilizing the procedures described in the previous examples, thecorresponding tablets and capsules may be prepared from Form I anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride, Form III anhydrous4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride or various mixtures thereof. In addition, utilizingthe procedures described in the previous examples, the correspondingtablets and capsules may be prepared from Form II hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride, Form IV hydrated4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride or various mixtures thereof. It is readilyappreciated by one of ordinary skill in the art that during theformulation process of the tablets and capsules described in thepreceding examples, interconversion between the above describedpolymorphs and pseudomorphs of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride may occur. In addition, it is understood that theresulting tablet or capsule may contain various mixtures of Forms I, II,III and IV of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid hydrochloride, hydrated and anhydrous.

1. A pharmaceutical composition in solid dosage form comprising, a) atherapeutically effective amount of a piperidinoalkanol compound offormula

wherein X is a number ranging from about zero to 5, or an optical isomerof the piperidinoalkanol compound, wherein the piperidinoalkanolcompound has a particle surface area of greater than about 1.0 m²/g; andb) at least one inert ingredient.
 2. The pharmaceutical compositionaccording to claim 1, wherein the inert ingredient is a disintegrant. 3.The pharmaceutical composition according to claim 1, wherein X is zero.4. The pharmaceutical composition according to claim 1 wherein at leastone inert ingredient is selected from the group consisting ofcroscarmellose sodium, lactose, microcrystalline cellulose,pregelatinized starch, gelatin, calcium carbonate, magnesium stearateand sodium starch glycolate.
 5. A pharmaceutical composition accordingto claim 1 wherein the particle surface area of the piperidinoalkanolcompound is about 2 to 10 m²/g.
 6. A pharmaceutical compositionaccording to claim 5 wherein the particle surface area of thepiperidinoalkanol compound is about 2 to 6 mg²/g.
 7. A pharmaceuticalcomposition according to claim 6 wherein the particle surface area ofthe piperidinoalkanol compound is about 2 to 4 mg²/g.
 8. Apharmaceutical composition in solid dosage form comprising: a) atherapeutically effective amount of a piperidinoalkanol compound of theformula:

wherein x is a number ranging from about zero to 5, or an optical isomerof the piperidinoalkanol compound; b) a first inert ingredient selectedfrom the group consisting of pregelatinized starch, gelatin, povidoneand a cellulose derivative; and c) a second inert ingredient selectedfrom the group consisting of methacrylic acid DVB, cross-linkedpolyvinylpyrrolidone, croscarmellose sodium, crospovidone and polacrilinpotassium.
 9. The pharmaceutical composition of claim 8, furthercomprising a third inert ingredient selected from the group consistingof magnesium stearate, calcium stearate, zinc stearate, stearic acid,talc and hydrogenated vegetable oil.
 10. The pharmaceutical compositionof claim 9, further comprising a fourth inert ingredient selected fromthe group consisting of lactose, starch, microcrystalline cellulose,powdered cellulose and mannitol.
 11. A pharmaceutical composition insolid dosage form comprising: a) a therapeutically effective amount of apiperidinoalkanol compound of the formula:

wherein x is a number ranging from about zero to 5, or an optical isomerof the piperidinoalkanol compound; b) a first inert ingredient selectedfrom the group consisting of pregelatinized starch, gelatin, povidoneand a cellulose derivative; and c) a second inert ingredient selectedfrom the group consisting of methacrylic acid DVB, cross-linkedpolyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate,crospovidone and polacrilin potassium; provided that the pharmaceuticalcomposition does not include a carbonate salt in an amount of more than1% by weight of the pharmaceutical composition.
 12. The pharmaceuticalcomposition of claim 11, wherein no carbonate salt is present.
 13. Thepharmaceutical composition of claim 11, further comprising a third inertingredient selected from the group consisting of magnesium stearate,calcium stearate, zinc stearate, stearic acid, talc and hydrogenatedvegetable oil.
 14. The pharmaceutical composition of claim 13, furthercomprising a fourth inert ingredient selected from the group consistingof lactose, starch and microcrystalline cellulose.
 15. A pharmaceuticalcomposition in solid dosage form comprising: a) a therapeuticallyeffective amount of a piperidinoalkanol compound of the formula:

wherein x is a number ranging from about zero to 5, or an optical isomerof the piperidinoalkanol compound; b) a first inert ingredient selectedfrom the group consisting of pregelatinized starch, gelatin, povidoneand a cellulose derivative; and c) a second inert ingredient selectedfrom the group consisting of methacrylic acid DVB, cross-linkedpolyvinylpyltolidone, croscarmellose sodium, sodium starch glycolate,crospovidone and polacrilin potassium; provided that the pharmaceuticalcomposition does not include concurrently a carbonate salt in an amountof more than 1% by weight of the pharmaceutical composition and apharmaceutically acceptable nonionic surfactant.
 16. The pharmaceuticalcomposition of claim 15, further comprising a third inert ingredientselected from the group consisting of magnesium stearate, calciumstearate, zinc stearate, stearic acid, talc and hydrogenated vegetableoil.
 17. The pharmaceutical composition of claim 16, further comprisinga fourth inert ingredient selected from the group consisting of lactose,starch and microcrystalline cellulose.
 18. A pharmaceutical compositionin solid dosage form comprising: a) a therapeutically effective amountof a piperidinoalkanol compound of the formula:

wherein x is a number ranging from about zero to 5, or an optical isomerof the piperidinoalkanol compound; b) a first inert ingredient selectedfrom the group consisting of pregelatinized starch, gelatin, povidoneand a cellulose derivative; and c) a second inert ingredient selectedfrom the group consisting of methacrylic acid DVB, cross-linkedpolyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate,crospovidone and polacrilin potassium; provided that the pharmaceuticalcomposition does not include concurrently a carbonate salt in an amountof more than 1% by weight of the pharmaceutical composition and apharmaceutically acceptable cationic surfactant.
 19. The pharmaceuticalcomposition of claim 18, further comprising a third inert ingredientselected from the group consisting of magnesium stearate, calciumstearate, zinc stearate, stearic acid, talc and hydrogenated vegetableoil.
 20. The pharmaceutical composition of claim 19, further comprisinga fourth inert ingredient selected from the group consisting of lactose,starch and microcrystalline cellulose.
 21. A pharmaceutical compositionin solid dosage form consisting essentially of: a) a therapeuticallyeffective amount of a piperidinoalkanol compound of the formula:

wherein x is a number ranging from about zero to 5, or an optical isomerof the piperidinoalkanol compound; b) a first inert ingredient selectedfrom the group consisting of pregelatinized starch, gelatin, povidoneand a cellulose derivative; and c) a second inert ingredient selectedfrom the group consisting of methacrylic acid DVB, cross-linkedpolyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate,crospovidone and polacrilin potassium.
 22. The pharmaceuticalcomposition of claim 21, further consisting essentially of a third inertingredient selected from the group consisting of magnesium stearate,calcium stearate, zinc stearate, stearic acid, talc and hydrogenatedvegetable oil.
 23. The pharmaceutical composition of claim 22, furtherconsisting essentially of a fourth inert ingredient selected from thegroup consisting of lactose, starch and microcrystalline cellulose.